Cost-effectiveness of Oral Protease Inhibitors Co-administration versus Pegylated Interferon-Α2b and Ribavirin Only for the Patients with Hepatitis C Genotype 1 in Kazakhstan Health Care Settings.

Background
The triple therapy including peginterferon, ribavirin and protease inhibitors was more effective compared to the combination of only peginterferon and ribavirin. This study aimed to assess the cost-effectiveness of triple treatment in either treatment-naïve and treatment-experienced patients in Kazakhstan.


Methods
A Markov model was created to assess long-term clinical advantages and the cost-effectiveness of the triple therapy from Kazakhstan payer perspective. Health state transition probabilities, pharmaceutical and other costs (according to the price in 2015), and utility rate were acquired from the published studies and publicly available sources. All used costs and benefits were discounted at 5% per year.


Results
Despite treatment background, the patients, receiving boceprevir and telaprevir, were estimated to experience less serious liver-disease complications, more life-years, and more QALYs compared to the patients having standard of care. For treatment-experienced group, boceprevir and telaprevir were dominant, with more QALYs. For all the groups of patients, incremental costs per QALY gained were between USD14995 and USD18075. The total average cost of boceprevir is slightly more costly than a standard duration of treatment with telaprevir, and so is the average cost per SVR. Extensive sensitivity analyses verified robust model results.


Conclusion
The inclusion of protease inhibitors to standard management for the therapy of patients with genotype 1 chronic HCV infection in Kazakhstan is predicted to be cost-effective using a typically applied willingness to pay threshold of USD37805 (3 times GDP per capita).


Introduction
Chronic hepatitis C virus (HCV) infection as a major public health threat is a major cause of chronic liver disease, liver disease-related deaths (LRD), hepatocellular carcinoma (HC). Naturally, it is the most frequent sign for liver transplanta-lence in Kazakhstan is from 0.6% to 0.7%, which refers to about 60000-70000 HCV-infected patients. Genotype 1 (G1) is more frequent (55%) in Kazakhstan and the most difficult to treat among six main HCV genotypes (5). Nowadays no vaccine against HCV exists; it is more effective to use the treatment pathways of decreasing the burden of the HCV infection. The primary objective of HCV treatment makes the virus undetectable for at least 6 months followed by the treatment that was known as a sustained virological response (SVR). The current clinical practiced to treat HCV infection is the combination of PEGylated interferon and ribavirin (PegIFN+RBV). The efficacy of double therapy depends on several factors like genotype, viral load, ethnic background, age, sex, fibrosis score and previous therapy (6). Efficacy of double therapy is about 40% in treatment-naïve (TN) patients with G1 and just 22% in treatmentexperienced (TE) patients with G1 (7). Two direct-acting antivirals (DAA), Boceprevir (BPV) and Telaprevir (TPV) have recently demonstrated significantly better treatment outcomes than traditional PegIFN+RBV for the treatment of G1 HCV infection. Both the DAA were approved in Europe and USA for using in the triple therapy of G1 HCV infection. The inclusion of BPV and TPV in the combination of PegIFN+RBV indicates the significant improvement of the SVR rates. SPRINT-2 and RE-SPOND-2 clinical trials (8,9) have shown the results that the SVR rate, gained by adding BPV to PegIFN+RBV, is equal to 67%-68% vs. 40% of TN patients and to 69%-66% vs. 21% in TE patients. ADVANCE and RELIAZE clinical trials (10,11) have shown that the SVR rate gained by adding TPV to PR is 69%-75% vs. 44% in TN patients and 54%-59% vs. 15% in TE patients. Therefore, the objective of our study was evaluation and comparison of the average cost per patient for BPV and TPV, and the cost per SVR using BPV, TPV, and standard of care (SOC) treatments as well as cost-effectiveness estimation in comparison with the latest clinical practice guidelines for the treatment of patients that have G1 HCV-infection in Kazakhstan.

Materials and Methods
Sustained virological response facts as a determination of antiviral treatment effectiveness were taken from the multicenter, placebo-controlled trials (ADVANCE (10), RELIAZE (11), RE-SPOND-2 (9) and SPRINT-2 (8)). The clinical trials, during which METAVIR scoring was applied, have determined the severity of hepatitis C disease; but fibrosis scores reporting is not obligatory in several cases in Kazakhstan. We have applied the patients' distribution by METAVIR scores according to the clinical trials (12,13) because of a lack of available data about fibrosis scores distribution in Kazakhstan. We have carried out semi-structured interviews in 2015 to determine the average age of the patient's cohort in the analysis. Three hundred thirty-seven patient reports from 14 centers were involved. Only complete therapy information was included in the analysis. The Kazakhstan HCV population took part in the study, which included 46% male and 54% female patients. The analysis has demonstrated that the average age of patients having HCV infection treated is 49.3 yr. The progression rates of the normal chronic HCV infection were taken (14). The baseline probability of HC development in patients with F3 state was approximated (15). Total annual number of HC increases with progression of cirrhosis. An excessive risk of HC and DC from compensated cirrhosis was approximated (16,17). The probability of liver transplantation necessity in advanced stages and mortality rates were derived from the Ministry of Health's database investigation, analysis, and other published data (5). Adverse events such as anemia are a major reason that the patients decline and reduce the dosage or stop therapy altogether (18). The patients received therapy-related anaemia in the clinical trials (8)(9)(10)(11) were managed by the decrease of ribavirin dose or anti-anemic therapy. In Kazakhstan, progressive ribavirin dose reduction is proposed as commonly used option for the management of HCV therapy-induced anemia (19). Accessible anti-anemic therapy reim-bursement is indicated in the management of HCV therapy-related anemia under Kazakhstani conditions. Moreover, there is no significant difference in SVR rates achieved in anemic patients receiving PI plus PR and using ribavirin dose reduction or anti-anemic therapy as well (20). Usually, anemia cases are managed by ribavirin dose reduction in Kazakhstan therapeutical practice; however, different anti-anemic therapy costs were analyzed. The direct medical costs of HCV disease include the cost of therapy, HCV overall health state-related costs as well as including the cost of liver transplantation. QALYs indicator is used regardless of whether the patient was treated or not, and for untreated patients, in particular, who have the disease progression and quantity of time spent in each of the HCV infection stages. All the costs and QALYs were discounted at 5%. We have forecasted the lifetime incidence of complications, total costs, and QALYs related to each management strategy. We also projected the incremental cost-effectiveness ratios (ICERs) for BPV-based and TPV-based regimens compared to PR treatment. The model has evaluated the cost-effectiveness of BPV-based and TPV-based therapy separately for TN and TE groups. We have calculated direct medical costs including drug acquisition costs that would be incurred by the healthcare payer in addition to medical cost offsets and adverse event costs (including treatment-related anemia). Indirect costs due to lost productivity were not included. Presently there is no any official cost-effectiveness threshold in Kazakhstan. Therefore, WHO-CHOICE (21) guideline around the cost-effectiveness threshold (3 times of gross domestic product (GDP) per capita) was taken into consideration when interpreting the benefits. Based on the 2015 World Bank data, 3 times of GDP per capita is USD 37 805. A constructed model simulates DAA-based therapy tactics and standard double therapy, permitted by the Ministry of Health of the Republic of Kazakhstan (MoH). Patients, not achieved the Hepatitis C virus indication in the blood, were shown in a Markov state-transition model diagram ( Fig. 1) as treatment-naïve (TN) as well as we indicated treatment-experienced patients (TE), already undergone any antivirus therapy. We used Markov model for analysis of the cost per patient for the treatment course and followup duration with the 4-wk intervals for the first 48 wk. Consider that the next 24 wk (follow-up time) as a one-time interval. Our model also used adverse event data, i.e., the proportion of patients, expected to experience adverse events common to PI and PR treatment (i.e., anemia, neutropenia, rash, and pruritus), taken from the indirect comparison by Cooper et al (22). The model design indicates the incidence of advanced liver disease (decompensated cirrhosis (DC), HC and liver transplantation. Therefore, it estimates the health outcomes and costs of various treatment approaches over the lifetime horizon in cohorts of patients with HCV in Kazakhstan. All the costs were calculated in Kazakhstan Tenge (KZT) at the exchange rate of US dollar (USD) in 2015 (1USD = 339,986KZT). To analyze the robustness of the model outcomes and impact of varying factors on costs and QALYs, both deterministic and probabilistic sensitivity analyses (PSA) have been conducted. Factors such as age, transition probabilities, treat-ment effectiveness, quality of life weights, health care costs, discount rates, implication of adverse events cost and mortality in health state of compensated cirrhosis were analyzed over a possible range. The base case input data and the lowerand upper boundaries of ranges were extracted from the published data while available. In the basic case scenario, all the costs and health outcomes were discounted at 5%, as specified in the Kazakhstan Health Technology Assessment Guidelines on processing health economic studies (23). Using the guideline, the sensitivity analysis was also completed based on the discount rates of costs and health outcomes applying the range of 3%-6% and 0%-6%, respectively.

Base-case Analysis
In TN patients, BPV-based triple combination treatment has predicted an increase in the life expectancy by 0.98 yr and QALY by 0.59 comparing to treatment with SOC treatment (Table 1).  The total average cost of standard treatment duration of using BPV is slightly cheaper than standard treatment duration of using TPV and, thus, it is the average cost per SVR. In addition, the total average cost of HCV therapy with BPV is significantly smaller than HCV therapy with TPV and, thus, it is the average cost per SVR. Additionally, the cost per SVR is comparable to HCV therapy using BPV and SOC, while the cost per SVR is more costly with TPV regimen. The observed differences can be defined by different scores where the costs are accumulated in the framework of different treatments. In TPV arm, all the patients receive expensive part of treatment within the first 12 wk. In BPV arm, the patients take only SOC for the first 4 wk of the therapy course, whereas BPV, the most expensive component of treatment, is administered throughout the remaining 44 wk. The discontinuation rates, and, thus, the proportion of patients, staying on treatment, play a role in the cost of BPV and TPV treatment as well. Most patients continue for 12 wk of the full 48-week therapy course, and, consequently, all of them receive a full course of TPV. By comparison, the patients, who have been discontinuing only between 12 and 48 wk, were going to receive a portion of the full course of BPV. Therefore, the total average costs are usually pulled in the direction of BPV favoring, because a full course of therapy is not wasted on those patients who discontinue. The costs related to clinical monitoring and AE management are both relatively small compared with the costs of SOC and BPV/TPV, and, thus, have a small relative impact on total average cost estimations.

Sensitivity Analyses
The deterministic sensitivity analysis (Table 3) demonstrates that the model outcomes are sensi-tive to changes in factors of efficacy (SVR rates), utilities and transition probabilities. The ICER, received from the model, exceeded the costeffectiveness threshold only when assuming the lower value of transition probabilities or the lower incremental health gain (SVR), achieved by BPV and TPV arms. The BPV-based regimen was cost-effective with a probability of 44% and 40% in TN and TE people respectively, and the TPV-based regimen was cost-effective with a probability of 48% and 43% in TN and TE groups respectively, at a willingness-to-pay value of USD 37805. Our results might lead to convenient implications for clinical practice. If its forecasts that HCV therapy with BPV and TPV, added to SOC, is more effective compared to SOC, it might appear beneficial from the societal perspective and for the patients. Patients generally prefer the most effective treatments, i.e., BPV or TPV rather than SOC. However, funding bodies should make decisions on that whether they should pay an extra money for the extra gain in the effectiveness. In this scenario, the cost of treating one person (by SVR) is comparable with SOC, the same as BPV or TPV added to SOC. This is a condition for each TN and TE patient. Thus, a higher level of efficiency and safety in the treatment of HCV G1 has shown interferon-free various modes of the therapy, reflected in new EASL recommendations (25). Moreover, in the view of the limited resources of health as well as the presence of specific contraindications of interferon-free therapy, using of BPV and TPV remains an important cost-effective option in the context of Kazakhstan.

Conclusion
The increased SVR rates, detected for BPV and TPV, compared with SOC alone, led to fewer HCV-related complications and LRD, likewise as improving the survival and quality-adjusted survival in the patient groups. Within the limitations of our model, BPV and TPV were estimated to be a cost-effective or cost-saving treatment option compared with SOC for the treatment of adults with chronic G1 HCV infection and compensated liver disease from the point of Kazakhstan payers view. Moreover, our model expects that high pharmaceutical costs of HCV-treatment for the patients, using BPV or TPV, compared with SOC alone, should be offset generally or completely, depending on the patient group, by savings in medical costs related to liver-disease complications.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.